Describing patterns of familial cancer risk in subfertile men using population pedigree data.

STUDY QUESTION: Can we simultaneously assess risk for multiple cancers to identify familial multicancer patterns in families of azoospermic and severely oligozoospermic men? SUMMARY ANSWER: Distinct familial cancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in familial cancer risk by both type of subfertility and within subfertility type. WHAT IS KNOWN ALREADY: Subfertile men and their relatives show increased risk for certain cancers including testicular, thyroid, and pediatric. STUDY DESIGN, SIZE, DURATION: A retrospective cohort of subfertile men (N = 786) was identified and matched to fertile population controls (N = 5674). Family members out to third-degree relatives were identified for both subfertile men and fertile population controls (N = 337 754). The study period was 1966-2017. Individuals were censored at death or loss to follow-up, loss to follow-up occurred if they left Utah during the study period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Azoospermic (0 × 106/mL) and severely oligozoospermic (<1.5 × 106/mL) men were identified in the Subfertility Health and Assisted Reproduction and the Environment cohort (SHARE). Subfertile men were age- and sex-matched 5:1 to fertile population controls and family members out to third-degree relatives were identified using the Utah Population Database (UPDB). Cancer diagnoses were identified through the Utah Cancer Registry. Families containing ≥10 members with ≥1 year of follow-up 1966-2017 were included (azoospermic: N = 426 families, 21 361 individuals; oligozoospermic: N = 360 families, 18 818 individuals). Unsupervised clustering based on standardized incidence ratios for 34 cancer phenotypes in the families was used to identify familial multicancer patterns; azoospermia and severe oligospermia families were assessed separately. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to control families, significant increases in cancer risks were observed in the azoospermia cohort for five cancer types: bone and joint cancers hazard ratio (HR) = 2.56 (95% CI = 1.48-4.42), soft tissue cancers HR = 1.56 (95% CI = 1.01-2.39), uterine cancers HR = 1.27 (95% CI = 1.03-1.56), Hodgkin lymphomas HR = 1.60 (95% CI = 1.07-2.39), and thyroid cancer HR = 1.54 (95% CI = 1.21-1.97). Among severe oligozoospermia families, increased risk was seen for three cancer types: colon cancer HR = 1.16 (95% CI = 1.01-1.32), bone and joint cancers HR = 2.43 (95% CI = 1.30-4.54), and testis cancer HR = 2.34 (95% CI = 1.60-3.42) along with a significant decrease in esophageal cancer risk HR = 0.39 (95% CI = 0.16-0.97). Thirteen clusters of familial multicancer patterns were identified in families of azoospermic men, 66% of families in the azoospermia cohort showed population-level cancer risks, however, the remaining 12 clusters showed elevated risk for 2-7 cancer types. Several of the clusters with elevated cancer risks also showed increased odds of cancer diagnoses at young ages with six clusters showing increased odds of adolescent and young adult (AYA) diagnosis [odds ratio (OR) = 1.96-2.88] and two clusters showing increased odds of pediatric cancer diagnosis (OR = 3.64-12.63). Within the severe oligozoospermia cohort, 12 distinct familial multicancer clusters were identified. All 12 clusters showed elevated risk for 1-3 cancer types. An increase in odds of cancer diagnoses at young ages was also seen in five of the severe oligozoospermia familial multicancer clusters, three clusters showed increased odds of AYA diagnosis (OR = 2.19-2.78) with an additional two clusters showing increased odds of a pediatric diagnosis (OR = 3.84-9.32). LIMITATIONS, REASONS FOR CAUTION: Although this study has many strengths, including population data for family structure, cancer diagnoses and subfertility, there are limitations. First, semen measures are not available for the sample of fertile men. Second, there is no information on medical comorbidities or lifestyle risk factors such as smoking status, BMI, or environmental exposures. Third, all of the subfertile men included in this study were seen at a fertility clinic for evaluation. These men were therefore a subset of the overall population experiencing fertility problems and likely represent those with the socioeconomic means for evaluation by a physician. WIDER IMPLICATIONS OF THE FINDINGS: This analysis leveraged unique population-level data resources, SHARE and the UPDB, to describe novel multicancer clusters among the families of azoospermic and severely oligozoospermic men. Distinct overall multicancer risk and familial multicancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in cancer risk by type of subfertility and within subfertility type. Describing families with similar cancer risk patterns provides a new avenue to increase homogeneity for focused gene discovery and environmental risk factor studies. Such discoveries will lead to more accurate risk predictions and improved counseling for patients and their families. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): R01 HD106112). The authors have no conflicts of interest relevant to this work. TRIAL REGISTRATION NUMBER: N/A.

iKNOWgynetics - A web-based learning concept to empower primary care gynecologists to participate in the care of patients with a family history of breast and ovarian cancer.

Familial cancer burden and genetics play an increasingly important role in the early detection and prevention of gynecological cancers. However, people with hereditary cancer risks are often identified late when they already have cancer. We aimed at developing and evaluating a training concept for primary care gynecologists-iKNOWgynetics-to improve their knowledge and awareness of genetic cancer syndromes and their ability to identify patients with increased familial cancer risks based on up-to-date evidence and current guidelines (in Germany, primary care includes all doctors treating patients on an outpatient basis without a clear separation of the expertise of the doctor or of their specialty). Starting off with a needs assessment among primary care gynecologists, we developed and evaluated an online training concept-using a web-based learning platform in combination with a live virtual seminar-to convey practice-relevant knowledge about familial cancer. After registration, participants get access to the web-based learning platform (www.iknowgynetics.de) to prepare for the virtual seminars and to use it as online reference to re-access the contents after the training. Evaluation included multiple-choice (MC) questions on knowledge and participants' self-efficacy to implement the acquired knowledge, which were administered in a pre-post design. Of 109 participants, 103 (94.5%) filled out pre- and post-questionnaires. Eighty-five participants were gynecologists in primary care from Berlin (81.2%) and Brandenburg (18.8%) and had an average of 24.1 years (SD = 8.5 years) of professional experience. After the training, participants answered significantly more knowledge questions correctly (M = 15.2 of 17, SD = 1.3) than before (M = 13.8 of 17, SD = 1.7) (p < 0.01) and felt more confident to be able to apply referral criteria for specialized counseling in practice (p < 0.001). The online-based training iKNOWgynetics considers the busy schedule of primary care gynecologists and supports them in acquiring practice-relevant information on familial cancer risks and on how to identify healthy persons at risk, which may ultimately help to improve the prevention of gynecological cancers. In future studies, the reported concept could be transferred to other entities.

Implementing mainstream genetic counseling within the area-wide network of the German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC): Satisfaction of primary care providers with the provided state-of-the-art training by the Cologne Center.

The German Cancer Society (Deutsche Krebsgesellschaft DKG) has published a position paper to address the challenges of cancer patient care in the era of genomic medicine. The German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) has implemented this recommendation in its care concept for families at risk. Core elements are the outcome-oriented evaluation of structured and standardized clinical measures and reporting recommendations derived therefrom to primary care providers and patients. A cross-sector network with certified breast cancer and gynecological cancer centers was founded in 2015, starting from the Cologne Center of the GC-HBOC. To guarantee the knowledge transfer for mainstream genetic counseling, the Cologne center has established an educational program for physicians and specialized nurses in order to pilot trans-sectoral knowledge transfer on risk assessment and risk-stratified care. It consists of face-to-face lectures with written knowledge test, attending a genetic case conference and genetic counseling sessions with the opportunity to counsel under supervision. The lectures were accompanied by a structured evaluation of the participants' satisfaction and feedback of the needs in mainstream genetic counseling. Thereby, the network ensures that genetic counseling and testing is provided according to state-of-the-art knowledge and allows physicians to participate in knowledge-generating care outside the university setting and patients to receive care close to home. After multiple feedback cycles to improve the educational program, the GC-HBOC, in cooperation with the German Cancer Society, has now adopted this concept and developed a common and uniform online curriculum funded by the Federal Ministry of Health. https://www.krebsgesellschaft.de/fortbildung-familiaerer-krebs.html.

Screening for colorectal cancer by full colonoscopy in first-degree relatives of colorectal cancer patients: a multicentric study by the Italian League for the Fight against Cancer.

Background: Colorectal cancer currently presents the third-highest incidence of cancers worldwide, making secondary prevention through screening programs for colorectal cancer, usually by Fecal Occult Blood Testing, an essential preventive medicine intervention. First-degree relatives of colorectal cancer patients are a particularly at-risk group, with indications to consider direct screening by full colonoscopy. Colonoscopy is considered the gold standard for diagnosing colorectal cancer, as it has high sensitivity and specificity, and is both a diagnostic and therapeutic tool. However, it requires significant organizational and financial resources, and has a small but relatively higher risk of complications as opposed to fecal occult blood testing. The present study aimed to assess the appropriateness of a screening program without age restrictions of CRC by full colonoscopy in asymptomatic, first-degree adult relatives of patients with colorectal cancer, aiming both to actively increase screening coverage and to determine the detection rate of precancerous lesions and colorectal cancer in this population. Study Design: Uncontrolled interventional study - colorectal cancer screening by full colonoscopy for at-risk population. Methods: The Italian League for the Fight against Cancer started a colorectal cancer screening program by full colonoscopy for first-degree relatives of colorectal cancer patients in 1998 in the province of Latina, Lazio Region, Italy. The program was expanded to the provinces of Rieti, Lazio Region, and Sassari, Sardinia Region, in 2014 and 2016 respectively, and was concluded in 2018. Subjects were actively and voluntarily recruited by the study's working group. Subjects that had already been subjected to a full colonoscopy in the preceding 5 years were excluded from this study. Identified neoplastic lesions were treated either directly or referred to the Day Hospital setting, and histologically diagnosed following World Health Organization guidelines. Results: In total, 2,288 subjects (age range 15-88, mean 52.3 yrs, M/F = 946/1,204) were screened by colonoscopy, of which 103 (4.5%) were incomplete and 2,173 (95.0%) complete, with data on colonoscopy performance missing for 12 participants. Out of 468 positive outcomes on colonoscopy, diagnosis for 422 (204M/173F), 19.4% of total subjects, was adenomatous polyps and 46 (20M/20F), 2.1% of total subjects, was colorectal cancer. Female sex was a protective factor against a positive test outcome, with a 35% reduction compared to male sex, with OR=0.64 95%CI (0.52-0.80). On the other hand, being over 50 years of age was found to be a risk factor, making a positive outcome more than twice as likely, with OR=2.3 95%CI (1.8-2.9). Subjects over 50 also had significantly more instances of multiple adenomas being found, however the size distribution of found adenomas was not significantly different between subjects under and over 50, despite size being a predictor of risk of neoplastic progression. Conclusions: Given the high detection rate of precancerous lesions and colorectal cancer in the studied population, it is our opinion that guidelines should continue to recommend earlier and more frequent screening in first-degree relatives of patients with colorectal cancer, and, barring the introduction of more cost-effective and/or lower risk procedures with a similar efficacy profile, maintain the use of colonoscopy as the main screening option.

Development and early-stage evaluation of a patient portal to enhance familial communication about hereditary cancer susceptibility testing: A patient-driven approach.

INTRODUCTION: Genetic testing for hereditary cancer syndromes (HCSs) can improve health outcomes through cancer risk mitigation strategies. Effective communication between tested individuals and their family members is key to reducing the hereditary cancer burden. Our objective was to develop a patient portal to improve familial communication for patients undergoing HCS genetic testing, followed by an early-phase evaluation. METHODS: The portal was developed following the completion of 25 semistructured interviews with individuals having undergone HCS susceptibility testing at BC Cancer. Following initial development, we recruited patients and healthcare providers to provide critical feedback informing portal refinement. Quantitative feedback was summarized using descriptive statistics, and qualitative feedback was synthesized by two reviewers who engaged in iterative discussion within the research team to prioritize recommendations for integration. RESULTS: The patient portal includes four key components consisting of (a) targeted educational information about hereditary cancer and HBOC syndrome associated risks and testing process overview, (b) a general frequently asked questions 'FAQ' page informed by the qualitative interviews, patient partner feedback, and consultation with the HCP, (c) guidance to support familial communication including a video developed with a patient partner describing their lived experience navigating the communication process and (d) a series of lay summaries of genetic test findings to support information transfer among family members. Thirteen healthcare providers and seven patients participated in user testing. Domains within which participant recommendations were provided included presentation, educational content and process clarification. CONCLUSIONS: This investigation demonstrates the value of continual integration of patient and provider preferences through the development of tools endeavouring to assist with complex genomics-informed decision-making. Our work aims to broaden the population-wide impact of HCS testing programs by improving communication processes between probands and their potentially affected family members. PATIENT OR PUBLIC CONTRIBUTION: This work involved a patient partner who was actively engaged in all aspects of the research investigation including protocol development, review and editing of all study documentation (including that of the previously published qualitative investigation), interpretation of results, as well as reviewing and editing the manuscript. Patient partners and healthcare professionals were recruited as research participants to provide critical feedback on the patient portal.

Intentions of Patients With Cancer and Their Relatives to Use a Live Chat on Familial Cancer Risk: Results From a Cross-Sectional Web-Based Survey.

BACKGROUND: An important prerequisite for actively engaging in cancer prevention and early detection measures, which is particularly recommended in cases of familial cancer risk, is the acquisition of information. Although a lot of cancer information is available, not all social groups are equally well reached because information needs and communicative accessibility differ. Previous research has shown that a live chat service provided by health professionals could be an appropriate, low-threshold format to meet individual information needs on sensitive health topics such as familial cancer risk. An established German Cancer Information Service is currently developing such a live chat service. As it is only worthwhile if accepted by the target groups, formative evaluation is essential in the course of the chat service's development and implementation. OBJECTIVE: This study aimed to explore the acceptance of a live chat on familial cancer risk by patients with cancer and their relatives (research question [RQ] 1) and examine the explanatory power of factors associated with their intentions to use such a service (RQ2). Guided by the Extended Unified Theory of Acceptance and Use of Technology (UTAUT2), we examined the explanatory power of the following UTAUT2 factors: performance expectancy, effort expectancy, social influence, facilitating conditions, and habit, supplemented by perceived information insufficiency, perceived susceptibility, perceived severity, and cancer diagnosis as additional factors related to information seeking about familial cancer. METHODS: We conducted a cross-sectional survey via a German web-based access panel in March 2022 that was stratified by age, gender, and education (N=1084). The participants are or have been diagnosed with cancer themselves (n=144) or have relatives who are or have been affected (n=990). All constructs were measured with established scales. To answer RQ1, descriptive data (mean values and distribution) were used. For RQ2, a blockwise multiple linear regression analysis was conducted. RESULTS: Overall, 32.7% of participants were (rather) willing, 28.9% were undecided, and 38.4% were (rather) not willing to use a live chat on familial cancer risk in the future. A multiple linear regression analysis explained 47% of the variance. It revealed that performance expectancy, social influence, habit, perceived susceptibility, and perceived severity were positively associated with the intention to use a live chat on familial cancer risk. Effort expectancy, facilitating conditions, information insufficiency, and cancer diagnosis were not related to usage intentions. CONCLUSIONS: A live chat seems promising for providing information on familial cancer risk. When promoting the service, the personal benefits should be addressed in particular. UTAUT2 is an effective theoretical framework for explaining live chat usage intentions and does not need to be extended in the context of familial cancer risk.

A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs.

BACKGROUND: We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale. RESULTS: Herein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs' tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic mutation landscape between TC in these dogs and human TC. Moreover, tumors with the GNAS p.A204D mutation had a significantly lower somatic mutation burden in these dogs. Somatic structural variant and copy number alterations were also investigated, but no potential driver event was identified. CONCLUSION: This study provides novel insight in the molecular mechanism of thyroid carcinoma development in dogs. German longhaired pointers carrying GNAS mutations in the tumor may be used as a disease model for the development and testing of novel therapies to kill the tumor with somatic mutations in the GNAS gene.

Dominant-negative pathogenic variant BRIP1 c.1045G>C is a high-risk allele for non-mucinous epithelial ovarian cancer: A case-control study.

BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case-control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3-444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5-1723.0; P < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2-106.5; P = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4-12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3-23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3-12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant-negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant-negative missense variants may confer higher risks than their loss-of-function counterparts.

Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management.

STUDY QUESTION: What is the load, distribution and added clinical value of secondary findings (SFs) identified in exome sequencing (ES) of patients with non-obstructive azoospermia (NOA)? SUMMARY ANSWER: One in 28 NOA cases carried an identifiable, medically actionable SF. WHAT IS KNOWN ALREADY: In addition to molecular diagnostics, ES allows assessment of clinically actionable disease-related gene variants that are not connected to the patient's primary diagnosis, but the knowledge of which may allow the prevention, delay or amelioration of late-onset monogenic conditions. Data on SFs in specific clinical patient groups, including reproductive failure, are currently limited. STUDY DESIGN, SIZE, DURATION: The study group was a retrospective cohort of patients with NOA recruited in 10 clinics across six countries and formed in the framework of the international GEMINI (The GEnetics of Male INfertility Initiative) study. PARTICIPANTS/MATERIALS, SETTING, METHODS: ES data of 836 patients with NOA were exploited to analyze SFs in 85 genes recommended by the American College of Medical Genetics and Genomics (ACMG), Geisinger's MyCode, and Clinical Genome Resource. The identified 6374 exonic variants were annotated with ANNOVAR and filtered for allele frequency, retaining 1381 rare or novel missense and loss-of-function variants. After automatic assessment of pathogenicity with ClinVar and InterVar, 87 variants were manually curated. The final list of confident disease-causing SFs was communicated to the corresponding GEMINI centers. When patient consent had been given, available family health history and non-andrological medical data were retrospectively assessed. MAIN RESULTS AND THE ROLE OF CHANCE: We found a 3.6% total frequency of SFs, 3.3% from the 59 ACMG SF v2.0 genes. One in 70 patients carried SFs in genes linked to familial cancer syndromes, whereas 1 in 60 cases was predisposed to congenital heart disease or other cardiovascular conditions. Retrospective assessment confirmed clinico-molecular diagnoses in several cases. Notably, 37% (11/30) of patients with SFs carried variants in genes linked to male infertility in mice, suggesting that some SFs may have a co-contributing role in spermatogenic impairment. Further studies are needed to determine whether these observations represent chance findings or the profile of SFs in NOA patients is indeed different from the general population. LIMITATIONS, REASONS FOR CAUTION: One limitation of our cohort was the low proportion of non-Caucasian ethnicities (9%). Additionally, as comprehensive clinical data were not available retrospectively for all men with SFs, we were not able to confirm a clinico-molecular diagnosis and assess the penetrance of the specific variants. WIDER IMPLICATIONS OF THE FINDINGS: For the first time, this study analyzed medically actionable SFs in men with spermatogenic failure. With the evolving process to incorporate ES into routine andrology practice for molecular diagnostic purposes, additional assessment of SFs can inform about future significant health concerns for infertility patients. Timely detection of SFs and respective genetic counseling will broaden options for disease prevention and early treatment, as well as inform choices and opportunities regarding family planning. A notable fraction of SFs was detected in genes implicated in maintaining genome integrity, essential in both mitosis and meiosis. Thus, potential genetic pleiotropy may exist between certain adult-onset monogenic diseases and NOA. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Estonian Research Council grants IUT34-12 and PRG1021 (M.L. and M.P.); National Institutes of Health of the United States of America grant R01HD078641 (D.F.C., K.I.A. and P.N.S.); National Institutes of Health of the United States of America grant P50HD096723 (D.F.C. and P.N.S.); National Health and Medical Research Council of Australia grant APP1120356 (M.K.O'B., D.F.C. and K.I.A.); Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Inovação grant POCI-01-0145-FEDER-007274 (A.M.L., F.C. and J.G.) and FCT: IF/01262/2014 (A.M.L.). J.G. was partially funded by FCT/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), through the Centre for Toxicogenomics and Human Health-ToxOmics (grants UID/BIM/00009/2016 and UIDB/00009/2020). M.L.E. is a consultant for, and holds stock in, Roman, Sandstone, Dadi, Hannah, Underdog and has received funding from NIH/NICHD. Co-authors L.K., K.L., L.N., K.I.A., P.N.S., J.G., F.C., D.M.-M., K.A., K.A.J., M.K.O'B., A.M.L., D.F.C., M.P. and M.L. declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer.

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC.

Changing patterns of referral into a family history clinic and detection of ovarian cancer: a retrospective 10-year review.

This study examines whether a change in the criteria for genetic testing for ovarian cancer risk changed the nature of referrals into our Familial Cancer service. This is a retrospective review of 273 women who underwent risk reducing surgery (RRS). The primary outcome was to establish whether there was an increase in women having RRS with a confirmed genetic mutation. Secondary outcomes included the incidence of occult cancer and of subsequent primary peritoneal cancer. The results showed an increase in women being offered RRS based on genetic diagnosis; 91% versus 32% before the criteria change. Four occult malignancies (1.5%) and two peritoneal cancers (0.7%) were noted.We have demonstrated a change in the nature of referrals to the familial cancer service from perceived risk to genetic diagnosis. We can now counsel women more accurately. With a defined risk we are enabling them to make an informed decision regarding risk reduction.

Bladder cancer risk associated with family history of cancer.

Twin studies suggest a familial aggregation of bladder cancer, but elements of this increased familial risk of bladder cancer are not well understood. To characterize familial risk of bladder cancer, we examined the relationship between family history of bladder and other types of cancer among first-degree relatives and risk of bladder cancer in 1193 bladder cancer cases and 1418 controls in a large population-based case-control study. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between family history of bladder cancer (defined as at least one first-degree family member with bladder cancer or a cancer of any other site). We also evaluated cancer aggregation of specific sites in family members. Participants with a first-degree relative with bladder cancer had nearly double the risk of bladder cancer (OR = 1.8, 95% CI 1.2-2.9) as those without a family history of bladder cancer. Risk was increased for having a sibling with bladder cancer (OR = 2.6, 95% CI 1.3-5.3) compared to no siblings with cancer. Bladder cancer risk was elevated when participants reported a first-degree relative with a history of female genital cancer (OR = 1.5, 95% CI 1.1-2.1), melanoma (OR = 1.9, 95% CI 1.02-3.6), and tobacco-associated cancer (OR = 1.3, 95% CI 1.06-1.6). These findings add to evidence of a familial predisposition to bladder cancer. Clarification of the aggregation of bladder cancer in families and with other cancer sites will be of interest as many loci and common polymorphisms related to bladder cancer have yet to be identified in large genomic studies.

Exome sequencing of familial adenomatous polyposis-like individuals identifies both known and novel causative genes.

Inherited polyposis syndromes are predominantly caused by pathogenic variants in APC and are linked to familial adenomatous polyposis (FAP). However, after clinical screening, 20%-30% of individuals diagnosed with FAP do not carry a pathogenic variant in APC (often categorised as FAP-like). Other known inherited adenomatous polyposis syndromes such as MUTYH, POLD1/E, or NTHL1-associated polyposis only account for, 3 a fraction of the remaining cases. A cohort of 48 individuals clinically diagnosed with a FAP-like phenotype was selected based on a strong family history of colorectal cancer and no previous pathogenic variant found in APC and/or MUTYH, by genetic screening. Using whole exome sequencing, FAP-like patients were found to carry pathogenic variants in MUTYH, APC, POLE and TP53, as well as DNA-repair genes and inflammation related genes. Additionally, a comprehensive assessment of copy number variation revealed two loci of interest that appeared to be associated with polyposis risk. In total, 6 out of 48 polyposis were explained through re-sequencing. This study highlights the potential role of DNA-repair as well as inflammation-related variants towards polyp development.

Two Cases of Possible Familial Chronic Myeloid Leukemia in a Family with Extensive History of Cancer.

CML is defined by the presence of an oncogenic fusion protein caused by a reciprocal translocation between chromosomes 9q and 22q. While our molecular understanding of CML pathogenesis has revolutionized drug development for this disease, we have yet to identify many predisposing factors for CML. Familial occurrence of CML has been rarely reported. Here, we describe 2 cases of CML in a 24-year-old woman and in her 73-year-old maternal great aunt. We describe genetic variants in these patients and report on their environmental exposures that may have contributed to CML pathogenesis. The possible familial association of these 2 cases of CML warrants further investigation into more definitive etiologies of this disease.

Cutaneous Expression of Familial Cancer Syndromes.

Genodermatoses are inherited syndromes with cutaneous manifestations. Some genodermatoses are associated with malignancy of internal organs and tissues. Early detection of the typical signs of these syndromes is important, because those lesions are a sign of underlying predisposition to extracutaneous neoplasms. The dermatologist has an important role in the early detection of these signs and syndromes, as early detection may affect the clinical course of the disease. We report here the characteristic cutaneous findings that dermatologists should be aware of in order to identify a genodermatosis with a possible associated malignancy. An updated overview of the pathogenesis and clinical findings of these syndromes is provided. Furthermore, surveillance protocols and treatment recommendations are explored.

Genetic variant interpretation: a primer for clinicians.

Clinicians beyond specialist genetic services are now able to order tests to interrogate the genetic basis of disease. Behind every genetic report lies a significant body of work that draws on decades of collaboration between clinicians, researchers and database curators. Understanding these advances in genetic variant interpretation may allow practising clinicians to develop a more nuanced appreciation of the role genetic variant interpretation can play in the diagnosis and management of heritable disorders. In this article, we consider genetic variant interpretation with reference to efforts to better understand variation in the mismatch repair genes and their relation to Lynch syndrome - the most common cause of hereditary colon cancer.

Linking population-based registries to identify familial cancer risk in childhood cancer.

BACKGROUND: Linked population-based registries provide a unique source for identification of new family cancer syndromes and for elucidating risk of early-onset cancer in close relatives of cancer patients. METHODS: Using the Finnish Cancer Registry, we identified 9078 probands who had been diagnosed with cancer at <21 years of age between 1970 and 2012. Siblings, offspring, parents, nephews, and nieces of probands were identified from the Population Registry. Childhood and young adult (ChYA) cancer diagnoses (age 0-39 years) in relatives were identified by linking to the Finnish Cancer Registry. The relative risk of ChYA cancer in family members of probands was estimated using standardized incidence ratios (SIRs). RESULTS: Among 58,010 family members of the 9078 probands, 363 ChYA cancers were diagnosed, 324 of which were expected (SIR, 1.12; 95% CI, 1.01-1.24). The risk of ChYA cancer was elevated both in offspring (SIR, 2.25; 95% CI, 1.51-3.24) and in siblings (SIR, 1.17; 95% CI, 1.01-1.36). Offspring of probands with retinoblastoma were at highest risk (SIR, 75.85; 95% CI, 32.75-149.45); risks were also elevated for siblings of probands with lymphoma (SIR, 1.62; 95% CI, 1.14-2.25). Known cancer predisposition syndromes were observed in 29 (66%) of 44 sibling pairs with cancers diagnosed at <21 years of age and in 20% of the 135 families with a childhood cancer proband whose sibling was diagnosed with a young adult malignancy. CONCLUSION: Linked population-based registry data indicate a modestly increased risk of ChYA in relatives of children with cancer. Some of the observed cancer clusters in the cohort suggest novel patterns and familial cancer syndromes.

Patterns of cancer family history and genetic counseling eligibility among African Americans with breast, prostate, lung, and colorectal cancers: A Detroit Research on Cancer Survivors cohort study.

BACKGROUND: Family history (FH) remains one of the strongest risk factors for many common cancers and is used to determine cancer genetic counseling (CGC) eligibility, but the understanding of familial cancer patterns in African Americans is limited. METHODS: This study evaluated cancer FH among African Americans with invasive breast cancer, prostate cancer, lung cancer, or colorectal cancer (CRC) in the Detroit Research on Cancer Survivors (ROCS) cohort. Associations between participant cancer type, site-specific FH, and meeting national guidelines for CGC were evaluated via logistic regression. Cancer FH patterns were evaluating via hierarchical clustering. RESULTS: Among 1500 ROCS participants, 71% reported at least 1 first-degree relative or grandparent with cancer. FHs of breast cancer, CRC, lung cancer, and prostate cancer were most common among participants with the same diagnosis (odds ratio [OR] for breast cancer, 1.14; P < .001; OR for CRC, 1.08; P = .003; OR for lung cancer, 1.09; P = .008; OR for prostate cancer, 1.14; P < .001). Nearly half of the participants (47%) met national CGC guidelines, and 24.4% of these participants met CGC criteria on the basis of their cancer FH alone. FH was particularly important in determining CGC eligibility for participants with prostate cancer versus breast cancer (OR for FH vs personal history alone, 2.91; 95% confidence interval, 1.94-4.35; P < .001). In clustering analyses, breast and prostate cancer FH-defined clusters were common across all participants. Clustering of CRC and breast cancer FHs was also observed. CONCLUSIONS: ROCS participants reported high rates of cancer FH. The high rate of eligibility for CGC among ROCS participants supports the need for interventions to increase referrals and uptake of CGC among African Americans.

Initial validation of a needs instrument for young people bereaved by familial cancer.

OBJECTIVE: This study aimed to validate the Bereaved Cancer Needs Instrument (BCNI), an instrument designed to assess the unmet psychosocial needs of adolescents and young adults (AYAs, 12-25 years) who have experienced the death of a parent or sibling to cancer. METHODS: In total, 335 participants aged 12 to 25 (M = 15.80, SD = 3.32) who had experienced the death of a parent (N = 297) or sibling (N = 38) from cancer took part in this study. Participants completed the BCNI, the Kessler-10 psychological distress scale (K10), and several items assessing the acceptability of the BCNI. RESULTS: Exploratory factor analysis indicated that a seven-factor structure best fit the BCNI, accounting for 56.65% of the variance in unmet psychosocial needs of cancer-bereaved AYAs. The measure had good psychometric properties, high levels of internal consistency for all domains, and correlated strongly with the K10 (r = .59, p < .001). Item response theory analysis demonstrated that the response scale was appropriate, with strong discrimination indices. Analyses also indicated the potential to reduce the BCNI from 58 items to a 37-item short-form, although this will require further validation. CONCLUSIONS: The BCNI is the first psychometrically validated instrument to identify the unmet psychosocial needs of bereaved AYAs who have experienced the death of a parent or sibling to cancer. The instrument can be used in research and health care settings to identify the unmet needs of young people bereaved by cancer and provide targeted support to reduce psychological distress.

Celebrating the career and contributions of Dr Henry T. Lynch (1928-2019).

This article celebrates the career of Dr Henry Lynch and his contributions to cancer genetics through his extensive research, clinical practice and his passion for personalising care by using a patient's genetic profile to determine management and treatment. Dr Lynch's contributions were momentous and continue to have relevance to medical practice, in particular in the fields of clinical genetics, medical oncology and gastroenterology.